Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Between 19% and 45% of inpatients with major depression have psychotic features, with greater prevalence in older patients. Although electroconvulsive therapy has well-established efficacy in the treatment of PD, its use is limited by several factors. As a result, the pharmacologic treatment of PD is common. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the pharmacologic treatment of PD. The recently completed Study of the Pharmacotherapy of Psychotic Depression (STOP-PD) was the first NIMH-funded randomized controlled trial (RCT) to examine the efficacy and tolerability of newer antidepressant and antipsychotic medications in the acute treatment of younger and older persons with PD. The combination of sertraline and olanzapine was significantly more efficacious than olanzapine combined with placebo. Both treatments were equally well tolerated, but were associated with clinically significant weight gain and elevation of lipids. Older persons, however, had significantly less weight gain than younger persons. Little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical relevance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder. The primary goal of this Renewal application, therefore, is to assess the risks versus benefits of continuing olanzapine in younger and older patients with PD, once the episode of depression has responded to treatment with sertraline and olanzapine. This goal will be addressed through a 36-week double-blind RCT, in which placebo is substituted for olanzapine in half the study group, following a period of sustained remission. We hypothesize that sertraline+olanzapine will be more efficacious than sertraline+placebo in preventing relapse of PD. This study provides the unique opportunity to systematically assess the effect of antipsychotic discontinuation (as opposed to switching from one antipsychotic to another) on olanzapine-related weight gain and metabolic disturbance. Additional innovative aims of the study are to examine age and genetic polymorphisms as predictors/moderators of treatment variability, potentially leading to more personalized treatment of PD, and to employ population pharmacokinetics to determine the magnitude and consistency of exposure to study drugs. Olanzapine is selected because it is the only atypical antipsychotic with established efficacy and tolerability in the treatment of both younger and older adults with PD . This research will be transformative, by providing clinicians with a much-needed evidence base to guide the continuation treatment of one of the most disabling and lethal psychiatric disorders. PUBLIC HEALTH RELEVANCE: This research will focus on psychotic depression (PD), one of the most severe, disabling, and lethal psychiatric disorders. The proposed study will address a question of profound clinical importance: what are the risks versus benefits of continuing treatment with antipsychotic medication, once an episode of PD has responded to combined antidepressant and antipsychotic pharmacotherapy? This randomized, placebo-controlled trial will assess whether continuation treatment with the atypical antipsychotic olanzapine, when given in combination with the antidepressant sertraline, prevents relapse of remitted PD;it will also assess the risks of this treatment with respect to weight gain and metabolic disturbance, side effects that have considerable public health significance.